Highly active antiretroviral therapy (HAART) suppresses HIV viral replication and restores immune function in HIV-infected individuals but HIV-1 can still persist in circulating, resulting CD4+ T cells. Immunotherapeutic strategies capable of targeting or eliminating the reservoir of HIV-1 infected, quiescent T cells represent an attractive possibility for control or eradication of AIDS. In particular vaccine stimulation of HIV-specific T cell responses during T cell recovery and reduced viral burden induced by anti-virals could result in reduction or elimination of residual virus and infected cells. Our recent studies demonstrate that particle-mediated DNA vaccination to the skin can induce CTL and protective immune responses against a highly pathogenic, heterologous SIV challenge in the macaque model for AIDS. These results suggest that DNA vaccination may be an effective strategy for therapy of HIV. We will evaluate the enterotoxins Vibrio cholerae Cholera toxin (CT) and E. coli heat-labile enterotoxin (LT) in the form of DNA as novel Th1 adjuvants for DNA vaccines. Our goal is to optimize DNA vaccine induction of peripheral blood CTL and T helper cell responses. We will test the potential for adjuvanted skin-administered DNA vaccines to induce or boost SIV-specific T cell therapy. These studies are designed to demonstrate feasibility of the approach and support development of skin administered DNA vaccines for therapy against HIV disease, including initiation of human clinical trials. Our specific aims are: 1) Test the hypothesis that co-delivery of SIV DNA vaccines with plasmids expressing bacterial enterotoxin adjuvants to the skin enhances antigen-specific CTL and Th cell responses in monkeys. 2) Measure the efficacy of DNA vaccination to the skin in combination with anti-retrovirals for therapy of SIV infection in rhesus macaques. 3) Develop therapeutic HIV DNA vaccine vectors for clinical trials and test immunogenicity in the murine model. 4) Test the immunogenicity of therapeutic HIV DNA vaccine vectors in asymptomatic HIV-1 infected human volunteers receiving HAART.